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Glutamate transporter
Glutamate transporters are neurotransmitter transporters that exist in the membranes of neurons and glial cells to remove excess amounts of the neurotransmitters glutamate and aspartate from the synapse. Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS), so glutamate transporters are required in the CNS to modulate its functioning. Since these excitatory amino acids cannot diffuse across the blood brain barrier, they require active transport, which is accomplished by glutamate transporters.Siegel, G J, Agranoff, BW, Albers RW, Fisher SK, Uhler MD, editors. 1999. Glutamate transporters. Basic Neurochemistry: Molecular, Cellular, and Medical Aspects 6th ed. Philadelphia: Lippincott, Williams & Wilkins. Accessed January 23, 2007. However, most glutamate is locally synthesised by glial cells.Pow DV and Robinson SR. 1994. Glutamate in some retinal neurons is derived solely from glia. Neuroscience. Volume 60, Issue 2, Pages 355-66. PMID 7915410. Retrieved on January 23, 2007. Glutamate transporters are also present in many other tissues such as bone and testes. Glutamate transporters are proteinaceous, membrane-bound pumps that resemble ion channels.Ganel R and Rothstein JD. 1999. Glutamate transporter dysfunction and neuronal death. Chapter 15 in Ionotropic glutamate receptors in the CNS. Jonas P and Monyer H, editors. Springer, New York. pp. 472-493. These transporters play the important role of regulating concentrations of glutamate in the extracellular space, keeping it at low levels.Han BC, Koh SB, Lee EY, Seong YH. 2004. Regional difference of glutamate-induced swelling in cultured rat brain astrocytes. Life Sciences, Volume 76, Number 5, Pages 573-583. PMID 15556169. Retrieved on January 23, 2007. After glutamate is released as the result of an action potential, glutamate transporters quickly remove it from the extracellular space to keep its levels low, thereby terminating the synaptic transmission.Shigeri Y, Seal RP, and Shimamoto K. 2004. Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. Brain Research Reviews, Volume 45, Issue 3, Pages 250-265. PMID 15210307. Retrieved on January 23, 2007. Without the activity of glutamate transporters, glutamate would build up and kill cells in a process called excitotoxicity, in which excessive amounts of glutamate acts as a toxin to neurons by triggering a number of biochemical cascades. The activity of glutamate transporters also allows glutamate to be recycled for repeated release.Zou JY and Crews FT. 2005. TNFα potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NFκ inhibition. Brain Research, Volume 1034, Issues 1-2, Pages 11-24. PMID 15713255. Accessed January 23, 2007. Locations These transporters are found in membranes of glial cells (astrocytes, microglia, and oligodendrocytes) as well as in endothelial cells and neurons.Anderson CM and Swanson RA. 2000. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia, Volume 32, Issue 1, Pages 1–14. PMID 10975906. Accessed January 23, 2007. The transporters in glia, particularly the various splice variants of GLT-1 play the largest role in regulating extracellular glutamate concentration.Shachnai L, Shimamoto K, and Kanner BI. 2005. Sulfhydryl modification of cysteine mutants of a neuronal glutamate transporter reveals an inverse relationship between sodium dependent conformational changes and the glutamate-gated anion conductance. Neuropharmacology, Volume 49, Issue 6, Pages 862-871. PMID 16137722. Retrieved on January 23, 2007. Types There are two types of glutamate transporters, those that are dependent on an electrochemical gradient of sodium ions and those that are not. Some sodium independent transporters such as the cystein-glutamate antiporter are localised to plasmamembrane of cells whilst others the are called vesicular transporters. Na+-dependent transporters are actually also dependent on K+ concentrations, and so are also known as 'sodium and potassium coupled glutamate transporters' or, in humans, 'excitatory amino acid transporters' (EAATs).Danbolt NC. 2001. Glutamate uptake. Progress in Neurobiology. Volume 65, Issue 1, Pages 1−105. PMID 11369436. Retrieved on January 23, 2007. Some Na+-dependent transporters have also been called 'high-affinity transporters', though their glutamate affinity actually varies widely. In humans, there are currently five known types of Na+-dependent glutamate transporters, EAATs 1–5 ( , , , , ) and three types of vesicular glutamate transporters, VGLUTs 1–3. ( , , ) In addition to these transporters, mitochondria also possess mechanisms for taking up glutamate that are quite distinct from membrane glutamate transporters. Na+-dependent transporters The sodium concentration-dependent types of transporter play a larger role than VGLUTs do in regulating glutamate concentration. These transporters couple the transport of glutamate to the symport and antiport of K+ and Na+, and hydroxyl ions. Kandel ER, Schwartz JH, Jessell TM. 2000. Principles of Neural Science, 4th ed., Page 287. McGraw-Hill, New York ISBN 0-8385-7701-6 In rodents such as rats, the homologs for humans' EAATs 1, 2 and 3 are called GLAST, GLT1, and EAAC1, respectively. EAAT1 and EAAT2 are mainly found in glial cells, EAAT3 and EAAT4 are mainly found in nerve cells and EAAT5 is a form principally localised to photoreceptors and bipolar neurons in the retina.Pow DV and Barnett NL. 2000. Developmental expression of excitatory amino acid transporter 5: a photoreceptor and bipolar cell glutamate transporter in rat retina. Neuroscience Letters. Volume 280, Issue 1, Pages 21-24. PMID 10696802. Accessed January 23, 2007. Vesicular transporters Vesicular glutamate transporters pack the neurotransmitter into synaptic vesicles so that they can be released into the synapse. VGLUTs are dependent on a proton gradient that they create by hydrolysing adenosine triphosphate (ATP). VGLUTs have only between one hundredth and one thousandth the affinity for glutamate that EAATs have. Also unlike EAATs, they do not appear to transport aspartate. Function In addition to removing excess glutamate from the synapse and packaging it into vesicles, glutamate transporters also recycle glutamate after it is used as a neurotransmitter. The glutamate is taken up into glia and converted into the amino acid glutamine, which lacks the potentially toxic excitatory effect of glutamate.Best, B. 1990. Brain Neurotransmitters. Accessed January 23, 2007. The glutamine is released from glia and transported back into neurons, converted back into glutamate, packaged into vesicles by VGLUTs, and stored for later release. This process is called the glutamate-glutamine cycle. Pathology Overactivity of glutamate transporters may result in inadequate synaptic glutamate and may be involved in schizophrenia and other mental illnesses. During injury processes such as ischemia and traumatic brain injury, the action of glutamate transporters may fail, leading to toxic buildup of glutamate. In fact, their activity may also actually be reversed due to inadequate amounts of adenosine triphosphate to power ATPase pumps, resulting in the loss of the electrochemical ion gradient. Since the direction of glutamate transport depends on the ion gradient, these transporters release glutamate instead of removing it, which results in neurotoxicity due to overactivation of glutamate receptors.Kim AH, Kerchner GA, and Choi DW. 2002. Blocking Excitotoxicity. Chapter 1 in: CNS Neuroproteciton. Marcoux FW and Choi DW, editors. Springer, New York. Pages 3 - 36. Loss of the Na+-dependent glutamate transporter EAAT2 is suspected to be associated with neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and ALS–parkinsonism dementia complex.Yi J-H and Hazell AS. 2006. Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury. Neurochemistry International. Volume 48, Issue 5, Pages 394-403. PMID 16473439. Accessed January 23, 2007. Also, degeneration of motor neurons in the disease amyotrophic lateral sclerosis has been linked to loss of EAAT2 from patients' brains and spinal cords. See also *Dopamine transporters *Norepinephrine transporters *Serotonin transporters *NMDA receptors *AMPA receptors *Kainate receptors *Metabotropic glutamate receptors References External links * Category:Membranes Category:Neurotransmitter transporters Category:Integral membrane proteins